P876: INCIDENTAL DISCOVERY OF PROBABLE PATHOGENIC GERMLINE VARIANTS IN MULTIPLE MYELOMA PATIENTS UNDERGOING SOMATIC GENOMIC PROFILING
Authors: S. Thibaud, T. Brander, M. Balwani, T. Mouhieddine, D. Melnekoff, O. Van Oekelen, A. Lagana, J. Houldsworth, A. Chari, J. Richter, L. Sanchez, S. Richard, C. Rodriguez, A. Rossi, H. J. Cho, S. Jagannath, K. Onel, S. Parekh
Journal: HemaSphere (2022)

Background: Next-generation sequencing (NGS) is increasingly used to characterize the somatic mutational landscape of patients with multiple myeloma (MM) and guide precision medicine approaches. Somatic genomic profiling (SGP) in cancer patients can lead to the incidental discovery of pathogenic or likely-pathogenic germline variants (PGVs) in ~4% of cases (PMID 26787237). Our previous analysis of whole exome germline data from 895 MM patients in the MMRF CoMMpass dataset showed ~8% of MM patients carry a PGV in a hereditary cancer gene (HCG), and identified shared characteristics among PGV carriers including younger age at diagnosis, higher likelihood of having family history of hematologic malignancy, higher likelihood of t(11;14) MM, and favorable outcomes (Thibaud et al, ASH 2021). Aims: The present study aims to assess the rate of detection of probable PGVs (PPGVs) in MM patients undergoing targeted SGP. Methods: We retrospectively reviewed results of 1,614 commercial NGS panels performed by a single genetic testing laboratory on bone marrow aspirates of 1,095 MM patients treated at our institution since 2015 who were not enrolled in the MMRF CoMMpass study. We considered individual variants to be PPGVs when all of the following criteria were met: 1) variant found in a panel of 106 well-established HCGs (same panel used in our prior study, but excluding TP53 given high rate of somatic mutations in MM); 2) variant unambiguously listed as pathogenic or likely pathogenic (P/LP) in ClinVar, or variant classified as “conflicting interpretations of pathogenicity” but reported by ≥2 CLIA-certified labs as P/LP; 3) variant allele frequency (VAF) >30% (per PMID 33236764); 4) variant detected in all available test reports for a given patient (and VAF >30% in all available test reports). Well known founder variants (FV) in specific populations were labeled as PPGV-FVs. Results: 95 MM patients (8.7%) had a genetic variant meeting criteria to be classified as a PPGV. Two patients had 2 distinct PPGV. PPGV were most commonly detected in the following HCGs (Table 1): APC (n=22), CHEK2 (n=20), ATM (n=7), BRCA1 (n=6), MUTYH (n=6). Of all PPGV carriers, 47 (49%) carried a PPGV-FV. Median VAF for PPGVs was 48.2% (range 30-85%). 34 PPGV carriers had serial NGS tests available (range 2-5 reports); in these patients, VAF standard deviation across serial measurements was <5% in 89% of cases. Taken together, these findings indicate a high likelihood that PPGV detected in these MM patients while undergoing tumor sequencing are indeed incidentally-discovered PGV warranting referral to a genetic counselor for consideration of confirmatory testing. Image:Summary/Conclusion: SGP of bone marrow aspirate in MM patients incidentally detected PPGV in well-established HCG in 8.7% of cases. These findings are consistent with those of our prior study, which found an 8.6% prevalence of PGV in newly-diagnosed MM patients. In MM patients undergoing SGP, detection of a mutation involving a HCG and with a VAF >30% should prompt referral to genetic counseling for confirmatory testing, as PGV detection can have clear implications for patients and their families.